A. Field of the Invention
The invention relates to the fields of biology and medicine. More particularly, the invention provides compositions and methods for the selective inhibition of expanded CAG-repeat containing disease proteins such as Huntingtin Disease (HTT) protein and Ataxin-3.
B. Related Art
Huntington's Disease (HD) is an autosomal dominant inherited disorder with an incidence of 5-10 per 100,000 individuals in Europe and North America (Borrell-Pages et al., 2004; Walker, 2007). HD is caused by the expansion of CAG trinucleotide repeats within the first exon of the huntingtin (HTT) gene, leading to disruption of protein function, and neurodegeneration (Gusella and MacDonald, 2006). Antisense oligonucleotides or siRNAs that reduce HTT expression have been proposed as a therapeutic strategy (Hasholt et al., 2003; Boado et al., 2002; Harper et al., 2005; Denovan-Wright and Davidson, 2006; DiFiglia et al., 2007) but most oligomers inhibit the mutant and wild-type protein expression indiscriminately. HTT is known to play an essential role in embryogenesis (Nasir et al., 1995), neurogenesis (White et al., 1997), and normal adult function in heterozygotes (Nasir et al., 1995), suggesting that agents inhibiting both mutant and wild-type HTT will induce significant side-effects. See Scholefield & Wood (2009) for a review.
One strategy for distinguishing mutant from wild-type alleles for HD and other neurological diseases uses siRNAs that target single nucleotide differences or deletions (Schwarz et al., 2006; Rodriguez-Lebron and Paulson, 2006; van Bilsen et al., 2008; Alves et al., 2008; Rodriguez-Lebron et al., 2009). These polymorphisms will often differ from patient to patient, complicating application of allele-specific RNAi in the clinic. Thus, there remains a need to identify agents that selectively inhibit mutant HTT production.
The inventors have previously demonstrated that single-stranded LNA or PNA oligomers that are fully-complementary to CAG repeat can inhibit expression of HTT or ataxin-3 in an allele-selective manner (Hu et al., 2009a; 2009b; 2009c). They also examined inhibition by fully-complementary duplex RNA, but observed little selectivity for inhibition of mutant versus wild-type HTT (Hu et al., 2009a).